Despite an increasing pool of living and non-heart beating donors, most kidneys that are finally transplanted are still derived from heart-beating, brain-dead donors. However, the state of brain death itself is an independent risk factor affecting successful organ transplantation, with grafts from brain-dead donors showing worse renal function and poorer survival rates after transplantation (Terasaki, P I, et al., N. Engl. J. Med., 333(6): 333-6 (1995); Matas, A J, et al., Transplantation, 69(1): 54-8 (2000)). In several animal models mimicking brain death and in brain-dead patients, systemic and local organ inflammation has been shown (Nijboer, W N, et al., Transplantation, 78(7): 978-86 (2004); Kusaka, M, et al., Transplantation, 69(3): 405-10 (2000); Hoeger, S, et al., Am. J. Transplant., 10(3): 477-89 (2010); Schuurs, T A, et al., Am. J. Transplant., 4(12): 1972-81 (2004)).
In previous studies it has been shown that local renal complement is activated in experimental and clinically brain-dead donors (Damman, J, et al., Transplantation, 85(7): 923-7 (2008)). Furthermore, it has been shown that systemic complement is activated in deceased human donors, predisposing the kidney graft to a higher risk of acute rejection after transplantation (unpublished data).
The complement system comprises more than 40 different proteins directly or indirectly mediating attack and elimination of microbes, foreign particles and altered self cells via three different pathways of activation: classical pathway, alternative pathway, and lectin pathway (see, The Complement System, 2nd revised edition, Rother et al. (eds); Springer Verlag (1998)). The complement system is a major component of innate immunity and is a central host defense against infection. Activation of the complement cascade via the classical pathway, involving antigen-antibody complexes, by the lectin pathway, or by the alternative pathway, involving the recognition of certain cell wall polysaccharides, mediates a range of activities including lysis of microorganisms, chemotaxis, opsonization, stimulation of vascular and other smooth muscle cells, degranulation of mast cells, increased permeability of small blood vessels, directed migration of leukocytes, and activation of B lymphocytes and macrophages. Inherent to complement activation is the generation of the anaphylatoxins C3a and C5a which have chemokinetic and pro-inflammatory properties (Walport, M J, N. Engl. J. Med., 344(14): 1058-66 (2001); Walport, M J, N. Engl. J. Med., 344(15): 1140-4 (2001)).
The membrane attack complex (MAC) is the final product of the activated complement cascade. It is a lytic multi-protein complex that is lethal to pathogens and, at sublytic levels, causes the release of cytokines and growth factors such as beta-FGF and VEGF from nucleated cells (e.g., smooth muscle cells, endothelial cells).
In renal transplantation, the important role of complement activation in the recipient has been extensively shown in models of renal ischemia-reperfusion-injury (IRI). In knock-out models of several complement components, renal IRI could be prevented (Zhou, W, et al. J. Clin. Invest., 105(10): 1363-71 (2000)). Moreover, local expression of complement C3 by the donor kidney negatively affects graft rejection and survival after transplantation (Pratt, J R, et al., Nat. Med., 8(6): 582-7 (2002)). Also post-transplantation, in rejecting grafts, complement is shown to be activated (Serinsoz, E, et al., Am. J. Transplant., 5(6): 1490-4 (2005)).
In the past, several strategies have been used to target renal complement activation in animal models of renal IRI and transplantation. Systemic administration of complement regulatory proteins, monoclonal antibodies against C5 or the C5a receptor (C5aR), or silencing of C3 and C5aR by small interfering RNA (siRNA) have been successful in preventing renal IRI or acute rejection (Arumugam, T V, et al., Kidney Int., 63(1): 134-42 (2003); Gueler, F, et al., J. Am. Soc. Nephrol., 19(12): 2302-12 (2008); Matthijsen, R A, Transplantation, 75(3): 375-82 (2003); Pratt, J R, Transpl. Immunol., 4(1): 72-5 (1996); Zheng, X, et al., Am. J. Transplant., 6(9): 2099-108 (2006); Zheng, X, et al., Am. J. Pathol., 173(4): 973-80 (2008).
However, it has not been previously known whether pre-treating an organ donor, in particular a brain-dead organ donor, to target donor systemic and local complement activation would be a viable therapy to improve the function or survival of the organ after transplantation from the donor to a recipient, and a persistent need for new therapeutic approaches to improve transplantation success is evident.